Autonomic Nervous System

Question 1

What does the ANS do?

Answer 1

• The ANS controls all vegetative (involuntary) functions
e.g. heart rate - blood pressure - GI motility - iris diameter
• The ANS is separate from the voluntary (somatic) motor
system
• It is entirely efferent (but is regulated by afferent inputs)

Question 2

What are the 2 anatomically defined divisions of the ANS?

Answer 2

Sympathetic

Parasympathetic

Question 3

Give a general description of the function of the sympathetic and parasympathetic nervous systems

Answer 3

The sympathetic nervous system responds to stressful situations
• “fight or flight” response
 heart rate  force of contraction  blood pressure

• The parasympathetic nervous system regulates basal
activities (e.g. basal heart rate) - “rest and digest”

Question 4

What are the anatomical divisions of the brain stem and spinal cord.

Answer 4

M = medullary
C = cranial
T = thoracic
L = lumbar
S = sacral

Question 5

Where do sympathetic neurones emerge?

Answer 5

And has 2 neurones in series
Sympathetic neurones emerge from thoracic and lumbar regions of spinal column
Travel a short distance - pass on info to a second neurone which travels from paravertebral column to target tissue

Question 6

Describe parasympathetic nerves

Answer 6

1. Originate in the lateral horn of the medulla [and sacral spinal cord]
2. Have long myelinated preganglionic fibres
3. Have short unmyelinated postganglionic fibres
4. Ganglia are located within the innervated tissues
5. Have actions that oppose the sympathetic nervous system

Question 7

Describe sympathetic nerves

Answer 7

1. Originate in the lateral horn of the lumbar and thoracic spinal cord
2. Have short myelinated preganglionic fibres
3. Have long unmyelinated postganglionic fibres
4. Ganglia are located in the paravertebral chain close to the spinal cord
5. Have actions that oppose the parasympathetic nervous system

Question 8

What are the main neurotransmitters in the ans?

Answer 8

ACh

NA

Question 9

What neurotransmitter do pre ganglionic neurones use

Answer 9

ALL PREGANGLIONIC NEURONES are cholinergic
Ie use ACh
They have nAChRs which are LGICs

Question 10

What neurotransmitter do parasympathetic post ganglionic neurones use and what type of receptors do that have?

Answer 10

• Parasympathetic post-ganglionic neurons are also cholinergic
• They release ACh which acts on muscarinic ACh (mACh) receptors in the target

Question 11

What neurotransmitter do sympathetic post ganglionic neurones use and what receptors do they have?

Answer 11

• Most sympathetic post-ganglionic neurons are noradrenergic i.e. they use noradrenaline (NA) as the principal neurotransmitter
• NA interacts with one of two major classes of adrenoceptors
• α-adrenoceptors and β-adrenoceptors
• These can be further subdivided into alpha 1 alpha 2 beta 1 beta 2 beta 3 subtypes

Question 12

How are different responses generates in different tissues by the same neurotransmitter

Answer 12

Different receptors can tailor the response

Question 13

Give examples of GPCRs

Answer 13

M1-M4 mAChRs and all adrenoceptors (a1-2 and b1-3)

Question 14

Name a type of specialises sympathetic post ganglionic neurone

Answer 14

• Some specialized sympathetic post-ganglionic neurons are cholinergic, not noradrenergic
► those innervating sweat glands, hair follicles (piloerection)

Question 15

Other than ACh and NA, what other eurotransmitters are Lund in the ANS?

Answer 15

Other transmitters are found in the ANS
• Non-Adrenergic, Non-Cholinergic (NANC) transmitters
• These may be co-released with either NA or ACh
Examples include:
ATP
nitric oxide (NO)
5-hydroxytryptamine (5HT; serotonin)
neuropeptides (e.g. VIP (vasoactive intestinal peptide), substance P)

Question 16

What is the enteric nervous system?

Answer 16

A third division of the autonomic nervous system? the enteric nervous system
Controls the gastrointestinal system, possessing ~1 x 108 neurons, and capable of operating independently of the CNS

Question 17

Describe sympathetic postganglionic neurones in the adrenal glands

Answer 17

• Sympathetic postganglionic neurons in the adrenal glands are different:
• They differentiate to form neurosecretory chromaffin cells
• Chromaffin cells can be considered as postganglionic sympathetic neurons that do not project to a target tissue
• Instead, on sympathetic stimulation these cells release
adrenaline (US name: epinephrine) into the bloodstream
• Chromaffin cells are present in the adrenal medulla
• Chromaffin cells are innervated by pre-ganglionic sympathetic neurons

Question 18

What does parasympathetic release of ach cause?

Answer 18

Heart (atria)
• bradycardia - SA node - M2
• reduced cardiac conduction velocity - AV node - M2

Smooth muscle
• bronchial/bronchiolar contraction - lungs - M3
• increased intestinal mobility/secretion - GI tract - M3
• bladder contraction (detrusor) and relaxation (trigone/sphincter) - GU tract - NO generation
• penile erection - GU tract - NO generation
• ciliary muscle and iris sphincter contraction - eye - NO generation

Glandular
• increased sweat/salivary/lacrimal secretion M1/M3

Question 19

What does sympathetic release of noradrenaline cause?

Answer 19

Heart (atria/ventricles)
• tachycardia (positive chronotropy) - SA node
• positive inotropy - ventricles

Smooth muscle
• arteriolar contraction/venous contraction (arteriolar relaxation in some vascular beds) - vasculature
• bronchiolar/intestinal/uterine relaxation - lungs/GI/GU
• bladder sphincter contraction - GU tract
• radial muscle contraction- eye

Glandular
• increased (viscous) secretion - salivary

Kidney
• renin release

Question 20

Define dysautonomia

Answer 20

Dysautonomia is an umbrella term for distinct malfunctions of the ANS

Examples include:
• Neurocardiogenic syncope
• Multiple system atrophy
• Postural orthostatic tachycardia syndrome (POTS)

Dysautonomia may occur as a primary disorder (where the ANS is the only system impacted) or occur secondarily to another condition (e.g. Parkinson’s disease- diabetes, etc.)

Question 21

What are the basic steps in neurotransmission

Answer 21

1. uptake of precursors
2. synthesis of transmitter
3. vesicular storage of transmitter
   * 4. degradation of transmitter
4. depolarization by propagated action potential
5. depolarization-dependent influx of Ca2+
6. exocytotic release of transmitter
7. diffusion to post-synaptic membrane
   * 9. interaction with post-synaptic receptors
   * 10. inactivation of transmitter
   * 11. re-uptake of transmitter
   * 12. interaction with pre-synaptic receptors

*most common sites of drug action

Question 22

Give an equation for acetylcholine synthesis

Answer 22

Acetyl CoA + choline (from diet) —> ACh + CoA
Catalysed by choline acetyltransferase
ACh is rapidly put into vesicles

Question 23

Give an equation for acetylcholine degradation

Answer 23

Acetylcholine —-> acetate + choline

Catalysed by acetylcholineesterase
Choline can be reused

Question 24

How are some drugs specific to autonomic ganglia? Give an example

Answer 24

Nicotinic acetylcholine receptors (nAChRs) at autonomic ganglia and the neuromuscular junction differ in structure. Therefore, some drugs have actions selectively at autonomic ganglia (e.g. the ganglion-blocking drug trimethaphan, which is used in hypertensive emergencies and to produce controlled hypotension during surgery).

Question 25

Are there drugs specific to mAChR subtypes?

Answer 25

There are 5 muscarinic acetylcholine receptor (mAChR) subtypes (M however, at present few subtype-selective mAChR agonists or antagonists are available clinically. Nevertheless, some newer agents do display limited tissue selectivity (e.g. the mAChR antagonist, tolterodine, which is used to treat “overactive bladder”).

Question 26

How ca the effects of ACh be enhanced?

Answer 26

The actions of endogenously released ACh can also be enhanced by AChE inhibitors (e.g. pyridostigmine, used to treat myasthenia gravis; donepezil, used to treat alzheimer’s disease).

Question 27

What does lack o selectivity of cholinergic drugs result in?

Answer 27

Unwanted side effects E.g. a non selective mAChR is likely to cause autonomic side effects such as decreasing heart rate/cardiac output, increasing bronchoconstriction and GI tract peristalsis, and increasing sweating and salivation

Question 28

What is SLUDGE syndrome?

Answer 28

SLUDGE is a mnemonic for the pathological effects indicative of massive discharge of the parasympathetic nervous system Salivation - stimulation of salivary glands Lacrimation - simulation of lacrimal glands Urination - relaxation of the urethral internal sphincter muscle and detrusor muscle contraction Defecation Gastrointestinal upset - smooth muscle tone changes causing GI problems, including diarrhoea Emesis - vomiting

Question 29

What causes SLUDGE?

Answer 29

SLUDGE syndrome is usually encountered in cases of  drug overdose  ingestion of “magic” mushrooms  exposure to organophosphorus insecticides (e.g. parathion), or nerve gases (e.g. sarin) The latter agents covalently-modify acetylcholinesterase, to irreversibly deactivate the enzyme and raise acetylcholine levels. The symptoms of SLUDGE are primarily due to chronic (over-) stimulation of muscarinic acetylcholine receptors, in organs and muscles innervated by the parasympathetic nervous system.

Question 30

What how can SLUDGE be treated?

Answer 30

SLUDGE may be treated with atropine, pralidoxime, or other anti-cholinergic agents. Atropine - Muscarnic receptor antagonist - blocks out overactivity of ach by blocking receptors Pralidoxime Binds to AChE reverses covalent modification

Question 31

Name some clinical uses of mAChR agonists

Answer 31

mACh receptor agonists and antagonists have some clinical uses, especially when they can be administered locally, rather than systemically. Muscarinic ACh receptor agonists: pilocarpine and bethanechol are respectively used to treat glaucoma and acutely to stimulate bladder emptying.

Question 32

Na,e some clinical uses of mAChR antagonists

Answer 32

Muscarinic ACh receptor antagonists: ipratropium and tiotropium are used to treat some forms of asthma and chronic obstructive pulmonary disease (COPD). Tolterodine , darifenacin and oxybutynin are used to treat overactive bladder.

Question 33

What occurs in an noradrenergic varicosity?

Answer 33

Post-ganglionic sympathetic neurons generally possess a highly branching axonal network with numerous varicosities, each of which is a specialized site for Ca2+-dependent noradrenaline release. Depolarisation of sympathetic pre ganglionic neurone Ap invades varicosity and passes onto next varicosity Release of NA - passes on Co ordinated release of NA - it then interacts with adrenoceptors Can be post junctional or on varicosity itself NA recaptured by an uptake mechanism Can then be reused (uptake into vesicles) or it can be metabolised Turnover of NA in varicosity Constant trickle of denovo synthesis to match constant trickle of metabolism

Question 34

Describe the synthesis of NA

Answer 34

Precursor is AA tyrosine - constant source - taken up by NA varicosity - converted by 2 intermediate steps Tyrosine converted to DOPA Then dopamine then NA 3 step enzymes that mediate the conversion Within the adrenal medulla noradrenaline is converted to adrenaline by the enzyme (phenylethanolamine N- methyltransferase)

Question 35

What happens following Ca2+ dependent release of NA?

Answer 35

• NA diffuses across the synaptic cleft and interacts with adrenoceptors in the post-synaptic membrane to initiate signalling in the effector tissue • NA interacts with pre-synaptic adrenoceptors to regulate processes within the nerve terminal – e.g. NA release • NA has only a very limited time in which to influence pre- and post-synaptic adrenoceptors as it rapidly removed from the synaptic cleft by noradrenaline transporter proteins

Question 36

Describe the termination step of NA transmission

Answer 36

Termination step - remove neurotransmitter at receptors Can only act at receptors if it is in the extravcelular space Uptake 1 (90-95% recaptured) - NA actions are terminated by re-uptake into the pre-synaptic terminal by a Na+-dependent, high affinity transporter Uptake 2 - NA not re-captured by Uptake 1 is taken up by a lower affinity, non-neuronal mechanism Recompartment into varicosity - no longer acts on receptors

Question 37

The majority of NA is reviseiculated - but what happens to the rest?

Answer 37

Within the pre-synaptic terminal NA not taken up into vesicles is susceptible to metabolism by two enzymes • monoamine oxidase (MAO) • catechol-O-methyltransferase (COMT)

Question 38

How can NA transmission be pharmacologically manipulated?

Answer 38

Drugs - agonists and antagonists Agents which are subtype selective Adrenoceptor agonists replace action of Na but activate only some of the receptors - Na stimulaes 9 receptors but these selectively stimulate some. Could selectively block out some adrenoceptors

Question 39

Give an example of how subtype selective adrenoceptor agonists/antagonists are used clinically

Answer 39

β2-adrenoceptor-selective agonists (e.g. salbutamol) are used in asthma to reverse/oppose bronchoconstriction. N.B. The β2-adrenoceptor-selectivity of such agents is important as it limits possible cardiovascular side-effects (e.g. positive inotropic and positive chronotropic actions) α1-adrenoceptor-selective antagonists (e.g. doxazosin) B1-adrenoceptor-selective antagonists (e.g. atenolol) are used to treat a number of cardiovascular disorders, including hypertension.